My career goal is to independently conduct basic and eventually translational research and train graduate and medical students. My main research interest, and the long-term goal of my career, is to improve treatments of psychiatric illnesses such as major depressive disorder. To this end, I plan to model disease and treatment in pharmacologically and/or genetically altered mice using behavioral approaches. I plan to then also use a combination of cellular, molecular and circuit-based techniques to determine the mechanisms underlying disease causes and successful treatments in these mouse models. The immediate goals for this proposal are to define the importance of a signaling pathway (TGFbeta), which fails to be activated in animal models of treatment-resistant depression and anxiety, in mediating the antidepressant response. My main expertise is in molecular, cellular and behavioral approaches to neuroscience. There are multiple major components of the training plan, mainly consisting of practical training in gene targeting technology to make mutant mice and the utilization of in vivo pharmacological manipulations. These components are necessary training to not only carry out the research plan as designed, but as practical skills tha will be required in my independent laboratory. Complementing the research training will be a more intellectual training aim designed to advance my understanding of translational approaches to neuropsychiatry. It is my ultimate goal to eventually take my basic research advances into a clinical setting, and the environment in the Department of Psychiatry at Columbia/RFMH can provide me with both the academic knowledge to implement such a goal and the surroundings in which I will interact directly with physician-scientists in a collaborative effort. This training component will consist of regular meetings with physician-scientists and coursework. Research Project Description: Elucidating the neurobiological basis of depression and determination of improved treatments is one of the foremost challenges for modern science. Severe forms of depression affect 2-5% of the U.S. population and mood disorders impact 7% of the world's population and rank among the top ten causes of disability. However, depression is highly heterogeneous in presentation and frequently exhibits high co-morbidity with other psychiatric and somatic deficits. Commonly used treatments, such as selective serotonin reuptake inhibitors (SSRIs), are not ideal since only a subset of patients achieve remission. In this proposal, we begin to assess this question by using a new strategy to model treatment-resistance in animals. We found significant activation of TGFbeta signaling in the dentate gyrus in responders to SSRI treatment, but not in untreated animals or non-responders. Based on this preliminary data and previous studies, the goal of this proposal is to further the understanding of molecular mechanisms underlying treatment-resistance in animals. Specifically we will fully examine the role of TGFbeta signaling in the dentate gyrus in mediating the effects of fluoxetine, and ask if activation of TGFbeta signaling is capable of converting non-responders to treatment into responders. Title of proposal: Mechanisms Underlying Treatment-Resistant Depression and Anxiety in Mouse Models Specific Aims: Aim 1 - To determine the effects of fluoxetine on TGFbeta signaling in the dentate gyrus in responders and non- responders to treatment Aim 2 - To determine if TGFbeta signaling in the dentate gyrus is required for mediating the effects of antidepressants Aim 3 - To determine if TGFbeta signaling activation in the dentate gyrus can convert non-responders to antidepressant treatment into responders PUBLIC HEALTH RELEVANCE: The goal of this proposal is to significantly advance the understanding of why many commonly used antidepressants yield a remission from depressive symptoms in only a subset of subjects. A better basic knowledge of why antidepressants don't always work could lead to potential therapeutic targets for new supplemental treatments that could be an improvement over current drugs.